Is EVC p.Arg340Gln (c.1019G>A) pathogenic?

EVC p.Arg340Gln (c.1019G>A) is classified Uncertain significance in EVC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-28). AlphaMissense: likely benign (0.0713); Ultra-rare (popmax 0.0131%, nfe); Associated with Inborn genetic diseases.

What condition is associated with EVC p.Arg340Gln (c.1019G>A)?

EVC p.Arg340Gln (c.1019G>A) is associated with Inborn genetic diseases, Ellis-van Creveld syndrome (ClinVar).

How common is EVC p.Arg340Gln (c.1019G>A) in the general population?

EVC p.Arg340Gln (c.1019G>A) is ultra-rare (popmax 0.0131%, nfe) (gnomAD).

What do computational predictors say about EVC p.Arg340Gln (c.1019G>A)?

AlphaMissense predicts likely benign (score 0.0713) — an in-silico prediction, not a clinical call.

EVC p.Arg340Gln

c.1019G>A · rs775052481 · VCV906716

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0713 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0131%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0713	likely benign
REVEL	0.01	strongly benign-leaning
SaProt	LLR -6.23	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.3	GERP 0.97, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 100 kb · p 1.2e-05 · regional, not allelic
Overall
CADD	15.56	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0131% European (non-Finnish) · 155/1,180,026 alleles

Filtering AF 0.0114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0107%

Overall 0.0104% 168/1,614,138 alleles · ultra-rare exomes 160/1,461,880 · genomes 8/152,258 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0131%	7,613
African / African-American	0.00533%	18,759
Admixed American	0.00333%	30,013
South Asian	0.00329%	30,359
Remaining individualsnot grpmax-eligible	0.0032%	31,254
East Asian	0.00223%	44,868
Finnishnot grpmax-eligible	0.00156%	64,024

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: EVC
Protein: p.Arg340Gln
Coding: c.1019G>A
MANE Select: NM_153717
dbSNP: rs775052481
Type: single nucleotide variant
Location: chr4:5748227 (GRCh38)
Gene constraint: LOEUF 1.134 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.49

Full EVC gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Ellis-van Creveld syndrome

Similar variants

EVC p.Arg340Ter Pathogenic/Likely pathogenic ★★ same residue
EVC p.Arg340Pro Uncertain significance ★ ⚠ same residue
EVC p.Arg340= Likely benign ★ same residue
EVC c.1098+1G>A Pathogenic/Likely pathogenic ★★ same condition
EVC c.175-2A>G Pathogenic/Likely pathogenic ★★ same condition
EVC c.1777-1G>A Pathogenic/Likely pathogenic ★★ same condition
EVC c.1777-2A>G Pathogenic/Likely pathogenic ★★ same condition
EVC c.1886+1G>C Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/evc-p-arg340gln (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown